Positron Emission Tomography Imaging of Thrombus The goal of this renewal proposal is to translate a recently developed fibrin-specific positron emission tomography (PET) probe, termed 64Cu-FBP8, for direct imaging of thrombus in patients. Thrombus plays a central role in a range of pathologies including ischemic stroke, myocardial infarction, pulmonary embolism, and deep vein thrombosis. The detection of thrombus with modern imaging techniques generally relies on the presence of filling defects, which are highly non-specific. Here we hypothesize that targeted molecular imaging of thrombus can be successfully performed in humans with a PET-detectable radiolabeled peptide. We further hypothesize that the accuracy of the probe will allow the presence/absence of thrombus in the left atrial appendage (LAA) to be imaged noninvasively. The current gold standard for the detection of LAA thrombus in patients with atrial fibrillation (AF) is transesophageal echo (TEE). While the experience with TEE is extensive, it is semi-invasive, requires sedation and prolonged monitoring, and does not prospectively identify patients with LAA thrombus before presentation to the hospital. A noninvasive alternative to TEE could improve patient comfort, streamline care, facilitate risk assessment in patients with AF and guide anti-coagulant management. This application, seeks to address this need through the clinical translation of 64Cu-FBP8for the detection of LAA thrombus in AF. In Aim 1 we will assess the pharmacokinetics, distribution, and elimination of 64Cu-FBP8 in healthy volunteers to establish safety, radiochemical dose, and to estimate an optimal time for thrombus imaging. In Aim 2 we will determine the accuracy of 64Cu-FBP8 PET to detect LAA thrombus in patients with AF, using recent TEE scans as the gold standard. In Aim 3 we will prospectively image AF patients to establish the negative predicative value of 64Cu-FBP8 PET and its potential as a noninvasive alternative to TEE. To further the utility of 64Cu-FBP8 and to enable its use at other sites, in Aim 4 we will develop a sterile kit formulation that will make the widespread production of 64Cu-FBP8 feasible. The proposed research will translate a new molecular imaging agent into humans and lay the foundation for subsequent multicenter trials. The burden of AF is increasing rapidly and the noninvasive detection of LAA thrombosis is a large and unmet need. The proposed research is thus of major relevance to both clinical medicine and general population health.